Vascular disease, because of its effects upon the heart, kidneys, extremities, and other vital organs, is a leading cause of morbidity and mortality in the United States and in most Western countries. In this regard, much has been learned about arteriosclerosis, atherosclerosis, and the lipidemias, with particular reference to cholesterol. In particular, there is convincing evidence of a reciprocal relationship between a high serum cholesterol and the incidence of atherosclerosis and its complications. Much interest has been expressed in recent years in reducing the level of serum cholesterol. However, some studies have shown that even radical reductions in dietary cholesterol achieves only a modest decrease of 10 to 15% in plasma cholesterol. Thus, it has been appreciated that further reductions in serum cholesterol will require other therapeutic measures, including the physiological inhibition of cholesterol synthesis in the body.
The enzymatic biosynthesis of cholesterol is a complex process, which requires altogether some 25 reaction steps. The pathway can be divided into three stages: (1) the conversion of acetic acid to mevalonic acid; (2) the conversion of mevalonic acid into squalene; and (3) the conversion of squalene into cholesterol. In the last stage of cholesterol biosynthesis, squalene is converted to squalene 2,3-epoxide via oxidation, a reaction catalyzed by squalene monooxygenase, also known as squalene epoxidase. The squalene 2,3-epoxide then undergoes cyclization to lanosterol, the first sterol to be formed.
The cyclization of 2,3-oxidosqualene to lanosterol is a key reaction in the biosynthesis of cholesterol in animals. The reaction is catalyzed by the microsomal enzyme 2,3-oxidosqualene lanosterol-cyclase. (See generally, Taylor, Frederick R., Kandutsch, Andrew A., Gayen, Apurba K., Nelson, James A., Nelson, Sharon S., Phirwa, Seloka, and Spencer, Thomas A., 24,25-Epoxysterol Metabolism in Cultured Mammalian Cells and Repression of 3-Hydroxy-3-methylglutaryl-CoA Reductase, The Journal of Biological Chemistry, 261, 15039-15044 (1986), incorporated herein by reference.)
In addition, it has recently been reported that certain compounds, such as allylamines, act as potent inhibitors of fungal squalene epoxidase. Fungal infections (mycoses) are found throughout the world. Only a few structural classes of compounds currently satisfy the demands of modern chemotherapy in their treatment and the search for new types of active substances is of major therapeutic importance. (See generally, Stutz, Anton, allylamine Derivatives-A New Class of Active Substances in Antifungal Chemotherapy, Angew. Chem. Int. Ed. Engl., 26, 320-328 (1987).) As inhibitors of squalene epoxidase in animals, the compounds of the present invention are believed to be useful in the treatment of fungal infections through the inhibition of cholesterol synthesis.